Neuroscience

The two infamous proteins, amyloid-beta (Aβ) and tau, that characterize advanced Alzheimer’s disease (AD), start healthy neurons on the road to cell death long before the appearance of the deadly plaques and tangles by working together to reactivate the supposedly blocked cell cycle in brain cells, according to research presented on Dec. 17 at the American Society for Cell Biology’s Annual Meeting in San Francisco.

Working in a mouse model of AD, George Bloom, PhD, of the University of Virginia (UVA) reports that neurons in AD start dying because they break the first law of human neuronal safety ⎯ stay out of the cell cycle.

Most normal adult neurons are permanently postmitotic; that is, they have finished dividing and are locked out of the cell cycle. In contrast, AD neurons frequently re-enter the cell cycle but fail to complete mitosis, and ultimately die. By considering this novel perspective on AD as a problem of the cell cycle, Dr. Bloom and colleagues at UVA and at the University of Alabama, Birmingham, have discovered what they call an “ironic pathway” to neuronal cell death. The process requires the coordinated action of both Aβ and tau, which are the building blocks of plaques and tangles, respectively. Dr. Bloom’s results show just how toxic the two proteins can be even when free in solution and not aggregated into plaques and tangles.

Using mouse neurons grown in culture, the UVA researchers found that Aβ oligomers, which are small aggregates of just a few Aβ molecules each, induce the neurons to re-enter the cell cycle. Interestingly, the neurons must make and accumulate tau in order for this cell cycle re-entry to occur. The mechanism for this misplaced re-entry into the cell cycle requires that Aβ oligomers activate multiple protein kinase enzymes, each of which must then attach a phosphate to a specific site on the tau protein.

Following up on the cell culture results, Dr. Bloom and colleagues confirmed that Aβ-induced, tau-dependent cell cycle re-entry occurs in the brains of mice that were genetically engineered to mimic brains with human AD. The mouse brains were found to accumulate massive numbers of neurons that had transitioned from a permanent cell cycle stop, known as G0 (G zero), to G1, the first stage of the cell cycle, by the time they were 6 months old. Remarkably, otherwise identical mice that lacked functional tau genes showed no sign of cell cycle re-entry, confirming the cell culture results.

Neuronal cell cycle re-entry, a key step in the development of AD, can therefore be caused by signaling from Aβ through tau. Thus, Aβ and tau co-conspire to trigger seminal events in AD pathogenesis independently of their incorporation into plaques and tangles. Most important, Dr. Bloom believes that the activated protein kinases and phosphorylated forms of tau identified in this study represent potential targets for early diagnosis and treatment of AD.

In the late Devonian period, roughly 365 million years ago, fish-like creatures started venturing from shallow waters onto land.

Among the various adaptations associated with the switch to land life was the conversion of fins into limbs. This transition allowed animals to both navigate aquatic habitats and walk on land.

We already know that fins and limbs share the same genetic program for their induction and early development. But due to their divergent morphological traits (form and structure), it was unknown how a fin could evolve into a limb.

But now, a paper published in the journal Developmental Cell by Renata Freitas and colleagues from the University of Andalusia (Seville, Spain), suggests the key to fin-to-limb transition lies in the regulation of the homeotic (responsible for the formation of body parts) gene hoxd13.

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Research from the Perelman School of Medicine at the University of Pennsylvania and Massachusetts General Hospital (MGH) reveals that sons of male rats exposed to cocaine are resistant to the rewarding effects of the drug, suggesting that cocaine-induced changes in physiology are passed down from father to son. The findings are published in the latest edition of Nature Neuroscience.

"We know that genetic factors contribute significantly to the risk of cocaine abuse, but the potential role of epigenetic influences – how the expression of certain genes related to addiction is controlled – is still relatively unknown," said senior author R. Christopher Pierce, PhD, associate professor of Neuroscience in Psychiatry at Penn. "This study is the first to show that the chemical effects of cocaine use can be passed down to future generations to cause a resistance to addictive behavior, indicating that paternal exposure to toxins such as cocaine can have profound effects on gene expression and behavior in their offspring."

In the current study, the team used an animal model to study inherited effects of cocaine abuse. Male rats self-administered cocaine for 60 days, while controls were administered saline. The male rats were mated with females that had never been exposed to the drug. To eliminate any influence that the males’ behavior would have on the pregnant females, they were separated directly after they mated.

The rats’ offspring were monitored to see whether they would begin to self-administer cocaine when it was offered to them. The researchers discovered that male offspring of rats exposed to the drug, but not the female offspring, acquired cocaine self-administration more slowly and had decreased levels of cocaine intake relative to controls. Moreover, control animals were willing to work significantly harder for a single cocaine dose than the offspring of cocaine-addicted rats, suggesting that the rewarding effect of cocaine was decreased.

In collaboration with Ghazaleh Sadri-Vakili, MS, PhD, from MGH, the researchers subsequently examined the animals’ brains and found that male offspring of the cocaine-addicted rats had increased levels of a protein in the prefrontal cortex called brain-derived neurotrophic factor (BDNF), which is known to blunt the behavioral effects of cocaine.

"We were quite surprised that the male offspring of sires that used cocaine didn’t like cocaine as much," said Pierce. "While we identified one change in the brain that appears to underlie this cocaine resistance effect, there are undoubtedly other physiological changes as well and we are currently performing more broad experiments to identify them. We also are eager to perform similar studies with more widely used drugs of abuse such as nicotine and alcohol."

The findings suggest that cocaine use causes epigenetic changes in sperm, thereby reprogramming the information transmitted between generations. The researchers don’t know exactly why only the male offspring received the cocaine-resistant trait from their fathers, but speculate that sex hormones such as testosterone, estrogen and/or progesterone may play a role.

Researchers at King’s College London have for the first time identified a defective gene at the root of Vici syndrome, a rare inherited disorder which affects infants from birth, leading to impaired development of the brain, eyes and skin, and progressive failure of the heart, skeletal muscles and the immune system.

Published in the journal Nature Genetics, the study identified a defect in the EPG-5 gene, indicating a genetic cause of the condition which was previously unknown. Researchers at King’s and Guy’s & St Thomas’ NHS Foundation Trust, part of King’s Health Partners, analysed the DNA of 18 infants with Vici syndrome and identified the inactivity of EPG-5 as a major cause of the condition.

Infants born with Vici syndrome inherit two copies of the defective gene, one from each parent. Although there are only around 50 known cases of the disorder across the world, researchers believe the precise incidence is unknown due to lack of awareness of this condition. Dr Heinz Jungbluth, from the Children’s Neuroscience Centre at St Thomas’ Hospital, who led the study along with Professor Mathias Gautel from the Cardiovascular Division at King’s, said: ‘Vici syndrome is likely to be under-diagnosed as there is potential for misdiagnosis, particularly when you consider the many different organ systems affected by Vici and the significant overlap with other, more common disorders.’

The study also highlighted the ‘autophagy’ process and the role of EPG-5 in causing this mechanism to fail. Autophagy is a highly regulated cellular process that removes damaged or unwanted components, which is crucial for the health of all cell types, including those involved in muscles, the immune system and brain development. Abnormalities in this process have been implicated previously in neurodegenerative conditions, but defects causing disorders of normal development such as Vici syndrome have rarely been reported. The researchers suggest that autophagy could play a key role in causing a range of disorders, offering the potential for treatment of other conditions. Dr Jungbluth said: ‘Although the condition is very rare, it is likely that insights provided by research into Vici syndrome will also be transferable to the diagnosis and therapy of neurodegenerative and neurodevelopmental disorders, and a wider range of primary muscle conditions.’

Professor Gautel added: ‘Having identified where this genetic defect occurs we are now able to explore potential interventions. For instance, there is the possibility of enhancing other pathways unaffected by the EPG-5 gene, or by preventing use of the defective pathway in the first place.’

As the defective gene is inherited from both the mother and father, there is also the possibility of screening families with a known history of Vici syndrome. Professor Gautel said: ‘Mothers could be offered preimplantation diagnosis, which involves removing a cell from an embryo when it is around three days old and testing it for genetic disorders, so that an unaffected embryo can be implanted into the mother’s womb, if necessary.’

Alzheimer’s disease is the most common form of dementia, affecting over 35 million people worldwide. It is generally assumed that the clumping of beta-amyloid (Aß) protein causes neuronal loss in patients. Medication focuses on reducing Aß42, one of the most common proteins and the most harmful. University of Twente PhD student Annelies Vandersteen is refining the current approach. She explains: “The results of my research provide a broader understanding of the processes that lead to Alzheimer’s disease and in this way may help to bring about new medication”.

The Aß protein occurs in the body in various lengths, ranging from 33 to 49 amino acids. The shorter varieties are regarded as ‘safe’, unlike the longer ones – Aß42 and longer – which are highly aggregating. Current therapeutic strategy tries to reduce the clumping of Aß42, and its harmful effects, by limiting the release of Aß42. Reducing Aß42 production at the same time results in a rise in Aß38 levels. Vandersteen comments: “One of the findings of my research is that small amounts of Aß38 can in fact increase or temper the clumping and toxic effects of longer Aß proteins. The processes that result in Alzheimer’s disease are determined by the whole spectrum of Aß proteins. So the picture is far less black and white than has been assumed so far, and less common forms of Aß are far less harmless than we thought.”

The study
Vandersteen examined the protein mixtures in a laboratory situation. She devised a series of experiments based on a computer-calculated hypothesis. The behaviour of the various Aß proteins and mixtures was studied in detail and described using various biophysical techniques. The influence of the various Aß proteins and mixtures on neurons was then studied in a cell culture.

A group of researchers at Chalmers University of Technology and the University of Gothenburg are now working on technology that can make MEG far more accessible. The vision is an MEG system that is simple and cheap enough to be available at every hospital, while furthermore providing totally new possibilities for fundamental investigations in brain research.

At the heart of the system is a new class of sensors that, unlike today’s MEG sensors, don’t require cooling to -269 Celsius. Instead, these work at -196 Celsius. This capability provides many advantages:

“One of them is the reduction of insulation between the sensors and the subject’s head,” says Dag Winkler, professor of physics at Chalmers. “The sensors can therefore get much closer to the brain so that one can take a more high-resolution picture of brain activity.”

With today’s technology, you can record activity from a patch of the brain that is roughly the size of a 1€ coin. With “Focal MEG” – MEG with liquid-nitrogen cooled sensors – the precision can be improved such that you’re recording from a patch of the brain that is a fraction of that size.

One example of what that can lead to is diagnosis of autism in children at a younger age – something that would be very meaningful considering how critical it is for these children to get the right help as early as possible.

“Another important advantage with Focal MEG is that the coolant the hardware requires is just liquid nitrogen”, Dag Winkler adds. “Today’s MEG requires liquid helium, which is extremely expensive. Furthermore, one can build the hardware with far more flexibility and less complication when using nitrogen instead of helium.”

The Gothenburg researchers have shown that Focal MEG works for advanced brain investigations. Using two sensors they developed, they have successfully recorded spontaneous brain activity –something that had never been done before with liquid-nitrogen cooled sensors. The ability to record spontaneous brain activity (as opposed to averaged activity from repetitive stimulation) is a solid indication that they can record more complicated brain activity.

“The prevailing assumption among MEG researchers has been that MEG with liquid-nitrogen cooled sensors isn’t feasible,” says Justin Schneiderman, assistant professor in biomedical engineering at the University of Gothenburg and MedTech West. “But now we’ve begun to expose holes in that assumption by demonstrating good sensitivity to two well-known brain waves from well-understood parts of the brain.”

The researchers have furthermore made an unexpected finding. They have recorded an uncharacteristically strong brain wave – the so-called theta rhythm – from the back of the brain. Today’s methods tend to find theta waves only in other parts of the brain.

“This is quite exciting,” says Mikael Elam, professor in clinical neurophysiology at the University of Gothenburg. “It may be an as-yet undetected type of brain signal that can only be found when one measures as close to the head as we do.”